rs1128127

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001002862.3(DERL3):c.632C>T(p.Ala211Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,584,594 control chromosomes in the GnomAD database, including 23,167 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 5575 hom., cov: 32)

Exomes 𝑓: 0.14 ( 17592 hom. )

Consequence

DERL3
NM_001002862.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.95

Publications

47 publications found

Variant links:

Genes affected

DERL3 (HGNC:14236): (derlin 3) The protein encoded by this gene belongs to the derlin family, and resides in the endoplasmic reticulum (ER). Proteins that are unfolded or misfolded in the ER must be refolded or degraded to maintain the homeostasis of the ER. This protein appears to be involved in the degradation of misfolded glycoproteins in the ER. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

DERL3 links:

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

SMARCB1 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
intellectual disability, autosomal dominant 15
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
rhabdoid tumor predisposition syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
SMARCB1-related schwannomatosis
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
familial multiple meningioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
schwannomatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SMARCB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.0331483E-4).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DERL3	NM_001002862.3 link	c.632C>T	p.Ala211Val	missense_variant	Exon 7 of 7	ENST00000318109.12	NP_001002862.1
SMARCB1	NM_003073.5 link	c.*2765G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000644036.2	NP_003064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DERL3	ENST00000318109.12 link	c.632C>T	p.Ala211Val	missense_variant	Exon 7 of 7	1	NM_001002862.3	ENSP00000315303.8
SMARCB1	ENST00000644036.2 link	c.*2765G>A		3_prime_UTR_variant	Exon 9 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34194

AN:

151598

Hom.:

5559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.179

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.278

Gnomad FIN

AF:

0.132

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.126

Gnomad OTH

AF:

0.214

GnomAD2 exomes

AF:

0.166

AC:

35198

AN:

211492

AF XY:

0.166

show subpopulations

Gnomad AFR exome

AF:

0.475

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.103

Gnomad FIN exome

AF:

0.128

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.153

GnomAD4 exome

AF:

0.141

AC:

202528

AN:

1432878

Hom.:

17592

Cov.:

AF XY:

0.144

AC XY:

102353

AN XY:

710772

show subpopulations

African (AFR)

AF:

0.475

AC:

15443

AN:

32544

American (AMR)

AF:

0.119

AC:

4707

AN:

39446

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

3903

AN:

24624

East Asian (EAS)

AF:

0.0674

AC:

2621

AN:

38896

South Asian (SAS)

AF:

0.271

AC:

22268

AN:

82032

European-Finnish (FIN)

AF:

0.132

AC:

6877

AN:

52190

Middle Eastern (MID)

AF:

0.214

AC:

1202

AN:

5628

European-Non Finnish (NFE)

AF:

0.124

AC:

135708

AN:

1098426

Other (OTH)

AF:

0.166

AC:

9799

AN:

59092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

8974

17948

26923

35897

44871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5168

10336

15504

20672

25840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.226

AC:

34240

AN:

151716

Hom.:

5575

Cov.:

AF XY:

0.224

AC XY:

16589

AN XY:

74144

show subpopulations

African (AFR)

AF:

0.460

AC:

18985

AN:

41312

American (AMR)

AF:

0.149

AC:

2277

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

522

AN:

3462

East Asian (EAS)

AF:

0.101

AC:

516

AN:

5132

South Asian (SAS)

AF:

0.277

AC:

1329

AN:

4806

European-Finnish (FIN)

AF:

0.132

AC:

1389

AN:

10544

Middle Eastern (MID)

AF:

0.228

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.126

AC:

8545

AN:

67888

Other (OTH)

AF:

0.212

AC:

447

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1189

2377

3566

4754

5943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.163

Hom.:

8102

Bravo

AF:

0.233

TwinsUK

AF:

0.122

AC:

454

ALSPAC

AF:

0.112

AC:

430

ESP6500AA

AF:

0.456

AC:

2009

ESP6500EA

AF:

0.126

AC:

1080

ExAC

AF:

0.165

AC:

19961

Asia WGS

AF:

0.200

AC:

698

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.072

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.76

MetaRNN

Benign

0.00040

MetaSVM

Benign

-0.92

PhyloP100

2.9

PROVEAN

Benign

-1.7

REVEL

Benign

0.084

Sift

Benign

0.27

Sift4G

Benign

0.26

Polyphen

0.0070

Vest4

0.014

ClinPred

0.010

GERP RS

2.3

Varity_R

0.043

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over